In the summer of 1939, Cloud worked as field assistant to A. Lincoln Washburn on Victoria Island in western Arctic Canada. For the rest of the year he taught at the Missouri School of Mines in Rolla. During 1941 to 1942 he returned to Yale University to continue work on brachiopod evolution as a Sterling Research Fellow. At the height of World War II, he was recruited to the United States Geological Survey to work on the wartime Strategic Minerals Program. He embarked on a field party to investigate manganese deposits in Maine during the summer of 1941. In 1943, he joined Virgil Barnes of the Texas Bureau of Economic Geology in the Ellenburger Project, studying the stratigraphy and sedimentology of this important early Paleozoic carbonate complex. He became chief of party for bauxite investigations in Alabama.[4]

After the war, in 1946, Cloud was appointed as Assistant Professor of Paleontology and Curator of Invertebrate Paleontology at Harvard University. In 1948 he returned to the U.S. Geological Survey to become chief of the Branch of Paleontology and Stratigraphy. He was chief of party to map and investigate the geology of Saipan in the Mariana Islands in the western Pacific. He became Chief Paleontologist from 1949 to 1959. In 1961 he was appointed as Chairman of the Department of Geology and Geophysics at the University of Minnesota. He established the School of Earth Sciences at that university, becoming its first Head. In 1965 he moved to the University of California, Los Angeles, as Professor of Biogeology, jointly with the Institute of Geophysics and the Department of Geology. In 1968 he transferred to the University of California, Santa Barbara campus, as full Professor. At UCSB he founded the Preston Cloud Research Laboratory, originally dedicated to paleomicrobiology and to studies of the first lunar geological samples from the Apollo 11 space mission. In addition, between 1974 and 1979 he was again a member of the U.S. Geological Survey based in Santa Barbara. He retired in 1974, but continued as Professor Emeritus.[8] He spent the rest of his life at UCSB.[1][1][7]

Cloud was a member of the National Academy of Sciences for thirty years, he was chairman of the Geology Section and occupied positions in its Council and Executive Committee. In 1967-69 he headed the Academy's "Committee on Resources and Man," whose alarming report "Resources and Man" introduced to a wider public, among other things, the work on energy-resources of his friend M. King Hubbert, and the Hubbert peak theory of Peak oil production. He also gave the Hadeangeologic eon, Earth's earliest, its name, using the Greek word for the Underworld to refer to a molten state of constant heat.

Cloud was the author of over 200 scientific and lay publications. Notably, his 1978 book, Cosmos, Earth, and Man: A Short History of the Universe, written for a general readership, has been called 'one of the first and finest presentations of "a more ample and more coherent picture of the world"' (Alles), and his 1988 Oasis in Space: Earth History from the Beginning a "comprehensive work of synthesis and reflection... a documented history of the earth and life on it... and an impressive capstone to his remarkable scholarship" (Crowell).

In 1990 special volume titled “Proterozoic Evolution and Environments” was published in the American Journal of Science in honour of Cloud's works.

University of California, Santa Barbara has a graduate student award named Preston Cloud Memorial Awards, which is given annually and carries minimum $200 for first-time attendance at a national or major meeting of a professional organization such as the Geological Society of America, American Geophysical Union, Association of American Petroleum Geologists, or for a student presenting a talk at such a meeting for the first time.[9]

Preston Cloud was the first scientist to systematically recognise the importance of the rich fossils of the Cambrian rocks in evolutionary terms. In order to explain the somewhat sudden appearance of diverse animals during the Cambrian Period, he invented the term "eruptive radiation" in his 1948 paper.[3] According to him, the earlier use of the term like "explosive" was misleading because the actual evolution could occur over a period of millions of years, and it "probably did not make a loud noise," he described, as implicated by the term. He postulated that adaptive radiation in any favourable ecological condition could always result in diversification of an original population into several distinct lineages, thus giving rise to eruptive evolution. Although his innovative thinking was largely ignored at the time, extensive research on the Cambrian fauna since the late 1970s, such as the fossils of the Burgess Shale, has established that the bio-geological event is a true documentation of the evolutionary origins of the animals, especially the body plans of modern animals.[2]

Cloud was a noted public speaker and symposium participant on the subjects of resources, the human future, origin of life and the primitive earth, and he regularly delivered many popular lectures.

Cloud was of small stature, and with a rather Asian-like complexion. During his service in World War II, as D. L. Peck, Director of the U.S. Geological Survey, noted in a letter dated January 29, 1941: "[Preston Cloud] created quite a stir among the locals who suspected that this person of slight stature, emerging from holes in the ground, must certainly be a Japanese spy in their midst.” At 5'6", he would often put his desk and chairs on 4-inch-high raisers so that, as he claimed, he could look down on others to show his authority.[10]

In graduate school, Preston was engaged to Mildred Porter. When Preston resigned from Harvard, they were divorced. In his time at Washington, he married Frances Webster, with whom he had three children, Karen, Lisa, and Kevin. The family moved to Minnesota in 1961, and though Preston and Frances were amicably divorced in 1965, two years later Preston relocated the entire family to Santa Barbara, California when he accepted a professorship at the University of California, Santa Barbara.

In Santa Barbara, Preston met and, in 1973, married Janice Gibson, an opera singer and mother of three children, Morgan, Dante, and Amanda. Preston and Janis remained together for the remainder of his life. Preston Cloud died at home, on January 16, 1991, of pneumonia, brought on as a complication of Lou Gehrig's disease.[11][12]